The present invention relates to novel substituted (thiophenyl-carbonyl)imidazolidinones, methods for their preparation, their use for the treatment and/or prophylaxis of diseases, as well as their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially of retroviral diseases, in humans and/or animals.
HIV (human immunodeficiency virus) causes a chronic persistent progressive infection. The disease proceeds via various stages from the asymptomatic infection to the pathological condition AIDS (acquired immunodeficiency syndrome). AIDS is the final stage of the disease caused by infection. The HIV/AIDS disease is characterized by a long clinical latency period with persistent viraemia which, in the final stage, leads to the failure of the immune defences.
The introduction of the anti-HIV combination therapy made it possible in the 1990s to effectively slow the down progression of the disease and thus to prolong substantially the life expectancy of HIV-infected patients (Palella, et al., N. Engl. J. Med. 1998, 238, 853-860).
The anti-HIV substances currently on the market inhibit the replication of the HI virus by inhibiting the essential viral enzymes reverse transcriptase (RT), protease or integrase, or the entry of HIV into the target cell (review in Flexner, Nature Reviews Drug Discovery 2007, 6, 959-966). There are two classes of RT inhibitors: nucleosidic and nucleotidic RT inhibitors (NRTI) act through competitive inhibition or chain termination in the DNA polymerization. Non-nucleosidic RT inhibitors (NNRTI) bind allosterically to a hydrophobic pocket in the vicinity of the active centre of the RT and bring about a conformational change in the enzyme. The currently available protease inhibitors (PI) block the active centre of the viral protease and thus prevent the maturation of newly produced particles into infectious virions. The only currently authorized integrase inhibitor Raltegravir binds in the active centre of the HIV integrase and prevents the integration of the proviral DNA into the host cell genome. Entry inhibitors (fusion inhibitors and coreceptor antagonists) prevent the HIV infection of cells by interacting with the HIV coat protein or by blocking the cellular coreceptors CCR5 or CXCR4.
Since monotherapy with the currently available anti-HIV medicaments leads in a very short time to a failure of the therapy owing to a selection of resistant viruses, usually a combination therapy with several anti-HIV substances from different classes takes place (highly active antiretroviral therapy=HAART; Carpenter, et al., J. Am. Med. Assoc. 2000, 283, 381-390).
Despite the advances in antiretroviral chemotherapy, recent investigations show that an eradication of HIV and, associated therewith, a cure of the HIV infection is not to be expected with the available medicaments. The latent virus remains in dormant lymphocytes and represents a reservoir for a reactivation and thus for a renewed spread of the virus (Finzi, et al., Nature Med. 1999, 5, 512-517; Ramratnam, et al., Nature Med. 2000, 6, 82-85). HIV-infected patients are therefore life-long dependent on an efficient antiviral therapy. Despite combination therapy, a selection of resistant viruses occurs after some time. Since resistance mutations characteristic for each therapeutic class accumulate, the failure of one therapy often means a loss of effect of the complete class of substances. This cross-resistance problem is most pronounced with the class of NNRTIs because in this case a single point mutation in the RT may often be sufficient to bring about a loss of effect of all NNRTIs (review in Kavlick & Mitsuya, Antiretroviral Chemotherapy (editor De Clercq E.), 2001, ASM Press, 279-312).
The development of resistances is usually favoured by the poor compliance of the patients which is caused by an unfavourable profile of side effects and a complicated dosage regimen for the anti-HIV medicaments.
There is thus a pressing need for novel therapeutic options for controlling an HIV infection. For this purpose, an urgent aim of HIV therapy research is to identify novel chemical lead structures which either address a novel target in the replication of HIV and/or are effective against the growing number of resistant clinical HIV isolates.
WO 91/19708 A1 discloses thiophenecarboxamides having pain-alleviating and anti-inflammatory effects. EP 0 065 295 A1 discloses thiophenecarboxamides for treating cardiovascular disorders. WO 94/27979 A1 discloses thiophenecarboxamides as modulators of peptides of the endothelin type. WO 02/00649 A1, WO 2006/062982 A2 and WO 2006/062984 A2 describe thiophenecarboxamides as inhibitors of various kinases. Certain thiophenecarboxamides as intermediates in the synthesis of polycyclic compounds are known from U.S. Pat. No. 5,627,203 and WO 03/014107 A1. Thiophenecarboxamides as inhibitors of protein prenylation are known from US 2004/0116425 A1 and WO 2004/016592 A1. WO 2005/035488 A2 describes thiophenecarboxamides as antagonists of the cannabinoid receptor CB1, and WO 2006/023462 A1 describes thiophenecarboxamides as antagonists of the histamine H3 receptor. Thiophenecarboxamides for the treatment of diseases caused by prions, cancer and disorders of the central nervous system and also for regulating stem cells are known from WO 2008/0903820 A1.